This review found that clinical benefits from treatment with lapatinib were limited to women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Lack of information about included populations, interventions and trial quality means that the reliability of the authors' conclusions is unclear and the results of the review should be interpreted with a substantial degree of caution.

Authors' objectives

To evaluate the clinical efficacy of lapatinib in patients with metastatic breast cancer of either human epidermal growth factor receptor-2 (HER2) status (HER2-positive or HER2-negative).

Searching

MEDLINE, EMBASE, BIOSIS Previews, were searched from 2001 to October 2009 for relevant studies; search terms were reported. Abstracts from the annual meetings of the American Society of Clinical Oncology (2006 to 2009) and the San Antonio Breast Cancer Symposium (2006 to 2008) were also searched. Reference lists from review articles and retrieved studies were checked to identify any further studies. It was not clear if there were any language restrictions.

Study selection

Randomised controlled trials (RCTs) in which lapatinib and placebo were compared in patients with metastatic breast cancer being treated with chemotherapy or endocrine therapy were eligible for inclusion.

Efficacy outcomes evaluated included progression-free survival, overall survival and disease stabilisation or response. Time to progression or event-free survival were assessed if data were not available on progression-free survival. Data collected for toxicity outcomes were serious adverse events (any toxicity grade 3 or more using the Common Terminology Criteria for Adverse Events) and discontinuation of treatment due to toxicity.

In the included open-label trial, all the included patients were HER2-positive; in the two double-blinded trials, only 15% and 17% of the patients were HER2-positive. More than half the patients received adjunctive endocrine therapy; the remaining patients received adjunctive chemotherapy. No additional participant or intervention details were reported.

The authors did not state how many reviewers performed the study selection.

Assessment of study quality

Trial quality components were assessed by two independent reviewers, and any disagreements were resolved by a third reviewer. However, the authors did not state which criteria were assessed.

Data extraction

Two reviewers independently extracted intention-to-treat data to calculate hazard ratios (HRs) for time-to-event data and odds ratios (OR), with 95% confidence intervals (CI) for both. Contact was made with the authors of individual trials in the event of missing data. Any disagreements between the reviewers were resolved by a third reviewer.

Methods of synthesis

Pooled hazard ratios, odds ratios and 95% confidence intervals were calculated using a random-effect model. There were no evaluations of statistical heterogeneity across the trials.

Three RCTs (n=2,264 patients) were included in the review. Two trials were multi-centre trials that used double blinding; one trial was an open-label trial.

Efficacy of lapatinib: The results of three RCTs showed significant benefits for the patients with HER2-positive breast cancer (n=705) after treatment with lapatinib in progression-free survival (HR 0.61, 95% CI 0.50 to 0.74), overall survival (HR 0.76, 95% CI 0.60 to 0.96), and in disease stabilisation or response (OR 2.23, 95% CI 1.57 to 3.18) compared with patients who were not treated with lapatinib. There were no significant differences between patients with HER2-negative breast cancer (n=1,559) who were treated with lapatinib and those who were not.

Toxicity of lapatinib (three RCTs; n=2,264 patients): Treatment with lapatinib was associated with a statistically significant increase in risk of serious adverse events (OR 1.64, 95% CI 1.21 to 2.23) and increase discontinuation of therapy due to toxicity (OR 2.28, 95% CI 1.04 to 4.97). The most frequently cited serious adverse events were diarrhoea, rash, arthralgia and fatigue. Sensitivity analyses showed non-significant trends towards increased serious adverse events and treatment when lapatinib was used with endocrine therapy rather than chemotherapy.

Authors' conclusions

Clinical benefits from treatment with lapatinib were limited to women with human epidermal growth factor receptor 2-positive breast cancer. Women with human epidermal growth factor receptor 2-negative breast cancer should not be treated with lapatinib outside of a clinical trial setting, because of the increased toxicity and lack of benefit in disease outcome.

CRD commentary

The review addressed a clearly defined question. Criteria for the inclusion of studies in the review were stipulated. Appropriate databases were searched; attempts were made to identify unpublished studies. It was unclear whether there were any language restrictions, which meant that there may be a risk of language bias. Steps were taken to minimise errors and bias in some parts of the study selection and data extraction.

The criteria details and results of the quality assessment were not published. This meant that the quality of the included trials remained unknown and the reliability of the results was unclear. In addition, there were few details provided about treatment durations and length of follow-up of the included trials reported in the review; there was also little detail provided on the patient populations and the interventions. The authors acknowledged some of the limitations of the review pertaining to the heterogeneity of the results found in the review.

Although the conclusions of the review were based on the evidence presented, there was a lack of information about trial quality and no follow-up data was presented. This means that the reliability of the authors' conclusions is unclear and the results of the review should be interpreted with a substantial degree of caution.

Implications of the review for practice and research

Practice: The authors stated that women with metastatic HER2-negative breast cancer should not be given lapatinib because there is no evidence of clinical benefit and lapatinib-treated patients were more likely to suffer serious adverse events and to discontinue treatment. The likelihood of experiencing serious adverse events should be discussed with women with HER2-positive breast cancer before treatment.

Research: The authors stated there is a paucity of data relating to the effects of lapatinib on quality of life. More data on survival and quality of life data are necessary to evaluate the clinical benefits of lapatinib in metastatic breast cancer.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.